Ia antigenic specificities are coded for by genes in the major histocompatibility complex (MHC) in both man and mouse, and in other species as well. These antigens occur, predominantly, on the surface of B lymphocytes, but genes within the I region (at least in the mouse) also code for well defined specificities found on some T cell subpopulations. We are studying these same specificities which occur in serum, and which represent similar determinants to those found on the surface of lymphocytes. We have demonstrated, using a rosetting system and a xenogeneic anti-Ia serum, that the same specificities detected in mouse sera are also present in human sera. These specificities are found on human B lymphocytes and a subpopulation of T cells and in addition, are found not to be associated with either Ig or beta 2 microglobulin molecules. It appears that the serum level of the Ia antigens may reflect the underlying degree of T cell function, as during delayed-type hypersensitivity responses, the level increases, whereas during suppression, the level of serum Ia falls. Chemical studies, conducted mainly in the mouse, have indicated that allo-antisera detect two cell surface moieties, whereas the xenogeneic system detects only one, which is most likely to be carbohydrate in nature. Studies are progressing to determine the chemical nature of the Ia material in man and the place, if any, of the measurement of serum Ia in both man and mouse with progressively growing tumors.